Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21
| Autor: | Steve Otieno, Li Ou, Martine F. Roussel, Yuefeng Wang, Richard W. Kriwacki, Jack Sublet, Rose Mathew, Jianhan Chen, Limin Xiao, John C Fisher |
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| Rok vydání: | 2011 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Magnetic Resonance Spectroscopy Cell division Protein Conformation Molecular Sequence Data Plasma protein binding Biology Article Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Protein structure Cyclin-dependent kinase Cyclins Humans Structure–activity relationship Amino Acid Sequence Molecular Biology 030304 developmental biology Cyclin 0303 health sciences Sequence Homology Amino Acid Eukaryota Cell Biology Cell cycle Cyclin-Dependent Kinases Cell biology 030220 oncology & carcinogenesis biology.protein Cell Division CDK inhibitor Protein Binding |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/nchembio.536 |
| Popis: | Traditionally, well-defined three-dimensional structure was thought to be essential for protein function. However, myriad biological functions are performed by highly dynamic, intrinsically disordered proteins (IDPs). IDPs often fold upon binding their biological targets and frequently exhibit “binding diversity” by targeting multiple ligands. We sought to understand the physical basis of IDP binding diversity and herein report that the cyclin-dependent kinase (Cdk) inhibitor, p21Cip1, adaptively binds to and inhibits the various Cdk/cyclin complexes that regulate eukaryotic cell division. Based on results from NMR spectroscopy, and biochemical and cellular assays, we show that structural adaptability of a helical sub-domain within p21 termed LH enables two other sub-domains termed D1 and D2 to specifically bind conserved surface features of the cyclin and Cdk subunits, respectively, within otherwise structurally distinct Cdk/cyclin complexes. Adaptive folding upon binding is likely to mediate the diverse biological functions of the thousands of IDPs present in eukaryotes. |
| Databáze: | OpenAIRE |
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